The present invention belongs to the field of medical devices and particularly relates to a vessel stent with multi drug-coatings covered with multiple layers of different drugs on the surface of the vessel stent or both the inside and outside surfaces of the vessel stent.
Since Sigwart, etc. applied intravascular metal stent to coronary artery the first time in 1987, it provided a good way to treat diseases that block vessels. However, the vessel stent restenosis remains the main reason that influences the effect of percutaneous coronary interventional treatment (PCI). Research has confirmed that the main reason that causes the vessel in-stent restenosis is a series of reactions, including the formation of thrombus induced after stent or saccule hurts vessel, the inflammatory reaction of cells, the migration and proliferation of smooth muscle cells and the flexibility recovery of vascular tissue happening in the process of implanting vessel stent.
To overcome the vessel in-stent restenosis, drug-eluting stent has shown unparalleled superiority in anti-stenosis performance. The existing drug-eluting stent mainly composes of a metal stent body, a carrier of drugs and drugs. In general, the drugs for resisting the vessel in-stent restenosis are coated on the surface of stent with the help of the carrier of drugs. However, the drug-coatings are all single coating, which causes no breakthrough in multiple links including coating area coating layers and drug compatibility or prevention of the happening of the vessel in-stent restenosis, thereby can not effectively control the release of drugs at different phases of endothelial repair and can not bring about good effect of treatment.
The object of the present invention is to provide a vessel stent with multi drug-coatings with more reasonable coating area and coating layers, drug compatibility, which can prevent the multiple links of the happening of restenosis, control the release of drugs at different phases of endothelial repair and has better effect of treatment.
The solution to achieve the object of the present invention is as follows:
A vessel stent with multi drug-coatings comprises a stent body and active drugs, characterized in that a portion of surface or whole surface of the stent body is covered with at least one kind and at least one layer of drug coating.
The active drugs is dissolved in the solution of biodegradable polymeric materials or non-biodegradable polymeric materials; the biodegradable polymeric materials comprise one of homopolymer or copolymer of glycolide, lactide and ε-caprolactone, and copolymer formed by coplymerizing one of homopolymer or copolymer of glycolide, lactide and ε-caprolactone with multi-functional group of amino acids, polylactic acid, chitin, chitosan and collagen; the non-biodegradable polymeric materials comprise poly butyl methacrylate, polyethylene vinyl acetate copolymer, ethylene or vinyl acetate copolymer, polypropylene or polyacrylonitrile copolymer, poly-ε caprolactone.
The active drugs may include anti-inflammatory immunosuppressive agents, anti-proliferative drugs, anti-cell migration drugs, endothelialization of coronary drugs and polypeptide drugs. The anti-inflammatory immunosuppressive agents include sirolimus, tacrolimus, everolimus, immunosuppressive agents ABT-578, dexamethasone and mizoribine; the anti-proliferative drugs include rapamycin, paclitaxel, actinomycin, angiopeptim, vincristine and their derivatives, statin drugs, 2-chlorodeoxyadenosin, arsenic trioxide (As2O3) and ribozyme; the anti-cell migration drugs include batimastat, halofuginone, C-protease inhibitor and probucol; the coronary endothelialization drugs include endothelial growth factor, estradiols, penicillamine cyclopeptides, monoclonal antibody CD133 and its fragments, monoclonal antibody CD31 and its fragments, monoclonal antibody CD34 and its fragments and nucleic acid drugs.
Monoclonal antibody CD34 and its fragments acting as coronary endothelialization drugs are arranged on the inside surface of the stent body and rapamycin acting as drug resistant to proliferation of smooth muscle cells r is arranged on the outside surface of the stent body (1). The rapamycin drug is dissolved in the acetone and tetrahydrofuran solution of the non-biodegradable polymeric materials including polybutyl methacrylate, polyethylene vinyl acetate copolymer their equally mixed mixture. The rapamycin drug may also be dissolved in the acetone and tetrahydrofuran solution of one of the biodegradable polymeric materials including homopolymer or copolymer of glycolide, lactide and ε-caprolactone, and copolymer formed by coplymerizing one of homopolymer or copolymer of glycolide, lactide and ε-caprolactone with multi-functional group of amino acids, polylactic acid, chitin, chitosan and collagen.
Rapamycin acting as drug resistant to proliferation of smooth muscle cells is arranged on the outside surface of the stent body and monoclonal antibody CD34 and its fragments acting as coronary endothelialization drugs may be arranged on the outside surface of the rapamycin. The said rapamycin is dissolved in the acetone and tetrahydrofuran solution of the non-biodegradable polymeric materials including polybutyl methacrylate, polyethylene vinyl acetate copolymer their equally mixed mixture, or dissolved in one of the biodegradable polymeric materials including homopolymer or copolymer of glycolide, lactide and ε-caprolactone, and copolymer formed by coplymerizing one of homopolymer or copolymer of glycolide, lactide and ε-caprolactone with multiple-functional group of amino acids, polylactic acid, chitin, chitosan and collagen. Same size holes with multiple crystal phase structure are prepared on the surface of the stent body by chemical corrosion, electrochemical corrosion, anodic oxidation, micro-arc oxidation or micro-arc nitridation.
The outside surface of the stent body with holes is covered with rapamycin acting as drug resistant to proliferation of smooth muscle cells. The said rapamycin drug is dissolved in the solution of biodegradable polymeric materials or non-biodegradable polymeric materials, or directly dissolved in organic solvents and then is coated on the outside surface of the stent body.
The inside surface of the stent body with holes is embedded with the drug that captures vascular endothelial progenitor cells and promotes the endothelialization of the surface of the stent.
The drug that captures vascular endothelial progenitor cells and promotes the endothelialization of the surface of the stent includes endothelial growth factor, estradiols, penicillamine cyclopeptides (cyclo-GpenGRGDSPCA), monoclonal antibody CD34 and its fragments, monoclonal antibody CD31 and its fragments, monoclonal antibody CD133 and its fragments and nucleic acid drugs. Preferably, the inside surface of the stent body 1 with holes 101 is embedded with monoclonal antibody CD34 and its fragments or penicillamine cyclopeptides 203.
The beneficial effects of the present invention include:
1. The surface of the bare stent is covered with multiple layers of different drugs or the inside and outside surfaces are covered with different drugs, which can not only speed up endothelialization of coronary, but also resist cell proliferation, resist the migration of smooth muscle cells, reduce the formation of thrombus and the inflammatory reaction of cells and recover the flexibility of vascular tissue.
2. Two or more kinds of drugs acting at different links are coated on the same stent, which play the role of co-resisting the vessel in-stent restenosis by multiple drugs and resist the different pathological phases of the in-stent restenosis.
3. Multi drug-coatings have good anti-inflammatory effect and can resist the proliferation of cells, resist the migration of smooth muscle cells, speed up endothelialization of coronary, prevent multiple links of the happening of restenosis and resist the release of drugs at different phases of endothelial repair.
4. Drugs resistant to proliferation of smooth muscle cells and coronary endothelialization drug antibody are coated on the stent at the same time and the well-combined drug coating can solve the problems of the vessel in-stent restenosis and the stent later period thrombus effectively, make the use more secure and bring better effect of treatment.
5. On the surface of the bare stent, same size holes with poly crystalline phases structure are prepared on the surface of the equipment body by chemical corrosion, electrochemical corrosion, anodic oxidation, micro-arc oxidation or micro-arc nitridation. The release of the drugs resistant to proliferation of smooth muscle cells on the outside surface can be controlled through the utilization of the size and depth of the holes. The coronary endothelialization drugs can be fixed through the utilization of the electrical property of the stent and the size and depth of the holes. The two drugs acting at the different links are assembled at a stent platform, through which the advantages of many kinds of drugs are shown and the problems of inflammatory and thrombus that may be induced by the carrier of prior drugs stent can be avoided at the same time.
The following examples are used to describe the present invention rather than limit the scope of the present invention.
A vessel stent with multi drug-coatings including a stent body 1 and active drugs 2, and metal materials such as 316L stainless steel, cobalt based alloy and nitinol may be selected for the stent body 1.
The biodegradable polymeric materials comprise one of homopolymer or copolymer of glycolide, lactide and ε-caprolactone, and copolymer formed by coplymerizing one of homopolymer or copolymer of glycolide, lactide and ε-caprolactone with multi-functional group of amino acids, polylactic acid, chitin, chitosan and collagen.
The non-biodegradable polymeric materials comprise polybutyl methacrylate, polyethylene vinyl acetate copolymer, EVA, polypropylene or polyacrylonitrile copolymer, poly-ε caprolactone.
The active drugs 2 are selected from four kinds of active drugs advantageously resisting the vessel in-stent restenosis, one of which is immunosuppressive agents with anti-inflammatory such as sirolimus, tacrolimus, everolimus, immunosuppressive agents ABT-578, dexamethasone and mizoribine; the second kind of active drug is the anti-proliferative drug such as rapamycin, paclitaxel, actinomycin, angiopeptim, vincristine and its derivatives, arsenic trioxide (As2O3), statin drugs, 2-chlorodeoxyadenosin and ribozyme; the third kind of active drug is anti-cell migration drug such as batimastat, halofuginone, C-protease inhibitor and probucol; the fourth kind of active drug is the drug speeding up coronary endothelialization such as endothelial growth factor (VEGF), estradiols, monoclonal antibody CD34 and its fragments, monoclonal antibody CD133 and its fragments, monoclonal antibody CD31 and its fragments and nucleic acid drugs (DNA, RNA and RNAi). Research and clinical analysis have confirmed that rapamycin drug 202 is an T cell inhibitor, as a kind of good anti-cell proliferation drug it can prevent T cell from transforming from G1 period to S period and prevent GO period of B cell; monoclonal antibody CD34 and its fragments 201 can capture vascular endothelial progenitor cells (EPC) by combining antigen with antibody, speed up the differentiation of vascular endothelial progenitor cells on the surface of the stent into endothelial cells, and promote the repair of endothelium; for arginine-glycine-aspartic acid (RGD) cyclopeptides and modified products penicillamine cyclopeptides (cyclo-GpenGRGDSPCA) 203 that have higher affinity to integrin α5β1 receptor than to αvβ3 receptor, monoclonal antibody CD34 and its fragments 201 can capture more endothelial progenitor cells (EPCs) by combing the receptor with ligand to make the EPCs differentiate into vascular endothelial cells on the surface of the stent quickly and therefore promote the repair of endothelium.
Thus, the inside surface of the stent body 1 with holes 101 is embedded with monoclonal antibody CD34 and its fragments or arginine-glycine-aspartic acid (RGD) polypeptide drug 203, and the monoclonal antibody CD34 201 and its fragments or arginine-glycine-aspartic acid (RGD) polypeptide drug 203 can be dissolved in phosphate buffer (pH 7.2˜7.4) or carbonate buffer (pH 9.6) and then be directly embedded in the holes 101 on the inside surface of the stent body 1. The outside surface of the stent body 1 is sprayed with drug 202 resistant to proliferation of smooth muscle cells, which can be sprayed with the help of non-biodegradable polymeric materials or biodegradable polymeric materials or being dissolved in tetrahydrofuran solution directly (the weight percent is 0.2˜5%).
Hereafter the preferable embodiments will be given:
While the invention has been described in terms of various specific embodiments and general description, it will be obvious to those skilled in the art that certain modification or improvement should be made to the invention as described without departing from the scope of the invention.
Basen on the prior vessel stent, the present invention utilizes physical or chemical method to corrode and form holes. According to their properties, the active drugs are dissolved in the solution of biodegradable polymeric materials or non-biodegradable polymeric materials, or directly dissolved in organic solvents (tetrahydrofuran, acetone, chloroform, etc.) or phosphate buffer (pH 7.2˜7.4) or carbonate buffer (pH 9.6), which can be coated on the stent body through drug coating methods such as spraying, dip-coating, roller coating, brush coating, sputtering and plasma polymerization to form the drug-coatings. The active drug monoclonal antibody CD34 and its fragments can capture vascular endothelial progenitor cells by combing antigen with antibody, speed up the differentiation of vascular endothelial progenitor cells on the surface of the stent into endothelial cells and promote the repair of endothelium. As a good anti-cell proliferation drug, the active drug, rapamycin can prevent T cell from transforming from G1 period to S period and prevent GO period of B cell; arginine-glycine-aspartic acid (RGD) cyclopeptides and its modified products-penicillamine cyclopeptides (cyclo-GpenGRGDSPCA) can capture more endothelial progenitor cells (EPCs) by combing the receptor with ligand to make the EPCs differentiate into vascular endothelial cells on the surface of the stent quickly and therefore promote the repair of endothelium. Thus, by the way of embedding the drugs mentioned above on the surface of the stent body with holes and utilizing the size and depth, the speed of release of drugs can be effectively controlled. At the same time, the coronary endothelialization drugs can be fixed through the utilization of the electrical property of the stent and the size and depth of the holes. The two drugs acting at the different links are assembled at a stent platform, through which the advantages of many kinds of drugs are shown, the problems of inflammatory and thrombus that may be induced by the carrier of prior drugs stent can be avoided, and the rate of formation of thrombus and the incidence of the disease of in-stent restenosis can be reduced effectively at the same time.
Number | Date | Country | Kind |
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200620148126.4 | Nov 2006 | CN | national |
200620166479.7 | Dec 2006 | CN | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/CN2007/002964 | 10/16/2007 | WO | 00 | 5/15/2009 |